Semaphorins were identified originally as guidance cues for developing neuronal axons. However, it is becoming clear that several semaphorins play important roles in the immune system. For instance, Sema4D (CD100) enhances activation of B cells and dendritic cells through its receptor, CD72. Sema4A is crucially involved not only in T cell priming but also in Th1/Th2 regulation. Additional semaphorins and related molecules also have distinct biological activities in the immune system. We here review the current topic of immunoregulatory semaphorins which could be targets for potenciation of, and intervention for immune response.